H. Asaru. Idaho State University.
FIGURE 7-47 THE SIDE EFFECTS PROFILE OF ANGIOTENSIN II The side effect profile of angiotensin II receptor antagonists generic careprost 3ml with mastercard medicine 2. RECEPTOR ANTAGONISTS Angiotensin II receptor antagonists are well tolerated. In contrast to the angiotensin-converting enzym e (ACE) inhibitors, cough and angioedem a are rarely (if at all) associated with this class of antihy- Side effects Mechanisms pertensive drug. Sim ilar to ACE inhibitors, however, hyperkalem ia and acute renal failure m ay occur in patients at risk. Hyperkalemia Blockade of angiotensin II Reduced aldosterone secretion Acute renal dysfunction Hypotension with impaired efferent anteriolar autoregulation Pharmacologic Treatment of Hypertension 7. The aim of anti- hypertensive therapy is risk reduction. Since the relationship between blood pressure and cardiovascular risk is continuous, the Category* Systolic (mm Hg) Diastolic (mm Hg) goal of treatm ent m ight be the m axim um tolerated reduction in blood pressure. There is controversy concerning what constitutes Optimal† <120 and <80 hypertension and how far systolic or diastolic blood pressure Normal <130 and <85 should be lowered, however. M ajor risk factors include *Not taking anithypertensive drugs and not acutely ill. For example, 160/92 mm Hg should be of cardiovascular disease in wom en younger than 65 and in m en classified as stage 2 hypertension, and 174/120 mm Hg should be classified as stage 3 hypertension. Isolated systolic hypertension is defined as systolic blood pressure of 140 younger than 55. Target organ dam age includes heart disease (left mm Hg or greater and diastolic blood pressure of less than below 90 mm Hg and ventricular hypertrophy, angina pectoris, prior myocardial infarction, staged appropriately (eg, 170/82 mm Hg is defined as stage 2 isolated hypertension). In addition to classifying stages of hypertension on the basis of average blood pressure Prevention and m anagem ent of hypertension-related m orbidity and levels, clinicians should specify presence of target organ disease and additional risk m ortality m ay best be accom plished by achieving a systolic blood factors. This specifically is important for risk classification. Recently, m ore aggressive blood Unusually low readings should be evaluated for clinical significance. Blood pressure control in the range of 125/80 m m H g (m ean arterial pressure of 108 m m H g) has been shown to slow the progression of renal disease [18,19]. This targeted blood pressure control m ay therefore be advisable in the m ajority of patients with hypertension. Regardless, each patient should be treated according to their cerebrovascular, cardiovascular, or renal risks; their specific pathophysiology or target organ dam age; and their concurrent disease states. A uniform blood pressure goal (target) probably does not exist for all hypertensive patients, and lower m ay not always be better. Risk group A (at least 1 risk factor, (TOD/CCD and/or Blood pressure stages (no risk factors, no not including diabetes; diabetes, with or with- (mm Hg) TOD/CCD)* no TOD/ CCD) out other risk factors)† High normal Lifestyle modification Lifestyle modification Drug therapy‡ (130–139/85–89) Stage 1 Lifestyle modification Lifestyle modification Drug therapy (140–159/90–99) (up to 12 months) (up to 6 months) Stages 2 and 3 Drug therapy Drug therapy Drug therapy (>160/≥100) Lifestyle modification should be adjunctive therapy for all patients recommended for pharmacologic therapy. FIGURE 7-50 CRITERIA FOR INITIAL DRUG THERAPY Selection of initial drug therapy. The Sixth Report of the Joint N ational Com m ittee on Prevention, Detection, Evaluation, and Treatm ent of H igh Blood Pressure (JN C VI) recom m ends that Reduce peripheral vascular resistance either a diuretic or a -blocker be chosen as initial drug therapy, No sodium retention based on numerous randomized controlled trials that show reduction in morbidity and mortality with these agents. Not all authorities No compromise in regional blood flow agree with this recom m endation. No stimulation of the renin-angiotensin-aldosterone system In selecting an initial drug therapy to treat a hypertensive patient, Favorable profile with concomitant diseases several criteria should be m et [6,9]. The drug should decrease Once a day dosing peripheral resistance, the pathophysiologic hallmark of all hypertensive Favorable adverse effect profile diseases. It should not produce sodium retention with attendant Cost effective (low direct and indirect cost) pseudotolerance. The drug should neither stim ulate nor suppress the heart, nor should it com prom ise regional blood flow to target organs such as the heart, brain, or the kidney. It should not stimulate the renin-angiotensin-aldosterone axis. Drug selection should consider concom itant diseases such as arteriosclerotic cardiovascular and peripheral vascular disease, chronic obstructive pulm onary disease, diabetes m ellitus, hypertensive cardiovascular disease, congestive heart failure, and hyperlipidemia. Drug costs, both direct and indirect, should be reasonable. It is readily apparent that no current class of antihypertensive drug fulfills all these criteria. Given the drugs that we have and their 6) thiazide-type diuretics [6,9,15].
The elevation of opioid peptide secretion may con- ceptors (316) buy careprost 3 ml line 10 medications. This analge- the anxiogenic effects of CCK-4 than are control subjects sic effect shows evidence of sensitization, because subse- (317,318). Although the mechanism un- Potentially consistent with these data, Pitman et al. In by endogenous opiate release during symptom provoca- PTSD, CCK-4–induced panic was associated with a lower tion). In the baseline state, the CSF -endorphin levels were ACTH response in the PTSD study subjects than in healthy abnormally elevated in PTSD relative to control samples controls, and cortisol concentrations increased in both the (328). The elevation in the corti- evening plasma -endorphin levels in a PTSD group versus sol concentrations attenuated more rapidly in the PTSD healthy control samples (329). Another study found no dif- group than in the control group. Neither PD that some patients with combat-related PTSD experience an subgroup showed significant changes in the plasma cortisol attenuation of their hyperarousal symptoms (331). The elevation preclinical studies in experimental animals have shown that of ACTH concentrations suggested that CRH secretion in- opiates potently suppress central and peripheral noradrener- creases in CCK-4–induced panic in PD (consistent with gic activity, these data appear compatible with the hypothe- preclinical evidence regarding the role of CRH in stress and sis that some PTSD symptoms are mediated by noradrener- anxiety and the interaction of CRH and CCK in modulat- gic hyperactivity (discussed earlier). EVIDENCE OF ALTERATION IN OTHER those of opiate withdrawal (170). NEUROTRANSMITTER SYSTEMS IN ANXIETY DISORDERS PTSD Panic Disorder Neuropeptide Y Benzodiazepine NPY administered in low doses intraventricularly attenuates Increased symptomatology with – ++ experimentally induced anxiety in a variety of animal benzodiazepine antagonist models (332). Consistent with these data, transgenic rats Decreased number of + +++/– that overexpress hippocampal NPY show behavioral insensi- benzodiazepine receptors tivity to restraint stress and absent fear suppression of behav- using SPECT-iomazenil or PET-flumazenil binding ior in a punished drinking task (333). In healthy humans Opiate subjected to uncontrollable stress during military training Naloxone-reversible analgesia + NS exercises, plasma NPY levels increased to a greater extent Reduced plasma β-endorphin + NS in persons rated as having greater stress resilience (334). Elevated levels of CSF β-endorphin + – During stress exposure, the NPY plasma levels were posi- Serotonin Decreased serotonin reuptake site ++ +/– tively correlated with plasma cortisol concentrations and binding in platelets behavioral performance, and they were negatively correlated Decreased serotonin transmitter – +/– with dissociative symptoms (334). In contrast, patients with combat-related Increased anxiogenic responses to /– PTSD had lower plasma NPY concentrations both at base- 5-HT agonists line and in response to yohimbine challenge than healthy Thyroid controls (336). In the PTSD group, the baseline NPY levels Increased baseline indices of + – thyroid function were inversely correlated with PTSD and panic symptoms Increased TSH response to TRH + – and with yohimbine-induced increases in MHPG and sys- Somatostatin tolic blood pressure (336). If this finding proves reproduci- Increased somatostatin levels at + – ble, it suggests that a deficit in endogenous NPY secretion baseline in CSF may be involved in the generation of anxiety and sympa- Cholecystokinin Increased anxiogenic responses to + +++ thetic autonomic symptoms in PTSD. CCK agonists –, One or more studies did not support this finding (with no positive Thyrotropin-Releasing Hormone and the studies), or the majority of studies do not support this finding; +/–, an equal number of studies support this finding and do not support Thyroid Axis this finding; +, at least one study supports this finding and no studies do not support the finding, or the majority of studies In the early twentieth century, Graves described cases in support the finding; ++, two or more studies support this finding, which thyroid hormone hypersecretion was associated with and no studies do not support the finding; +++, three or more studies support this finding, and no studies do not support the anxiety, palpitations, breathing difficulties, and rapid heart finding; +++/–, three or more studies support this finding, and rate in persons recently exposed to traumatic stress. Never- one study does not support the finding; cAMP, cyclic adenosine 3, 5-monophosphate; CCK, cholecystokinin; CSF, cerebrospinal fluid;′ ′ theless, systematic epidemiologic studies of the relationship NS, not studied; PTSD, posttraumatic stress disorder; SPECT, single between stress and thyroid disease have not been conducted. The most straightforward forms of respira- tory stimulation that produce panic anxiety produce eleva- tions of carbon dioxide pressure (hypercapnia). Thus, panic Respiratory System Dysfunction in Panic attacks can be consistently induced in patients with PD by Disorder rebreathing air, inhaling 5% to 7% carbon dioxide in air Associations between respiratory perturbation and acute (343,344), or inhaling a single deep breath of 35% carbon anxiety have been demonstrated in PD, in which various dioxide (345,346). Other panicogenic chemical challenges forms of respiratory stimulation consistently produce panic have also been hypothesized to induce anxiogenic effects Chapter 63: Neurobiological Basis of Anxiety Disorders 921 through respiratory stimulation (340,341,347). Although enous mechanisms for modulating the neural transmission the panicogenic mechanism of intravenous administration of information about aversive stimuli and responses to such of sodium lactate remains unclear, it may also involve respi- stimuli. Novel treatments being developed to exploit the ratory stimulation (339,340). Nevertheless, these pathophysiology of specific anxiety disorders and the neural data partly depend on subjective ratings of dyspnea during pathways involved in anxiety and fear processing, the devel- stress or respiratory stimulation, and the mechanisms under- opment of therapeutic strategies that combine both types lying this sensitivity remain unclear. One possibility is that of approaches may ultimately provide the optimal means this hypersensitivity reflects an overall sensitivity to somatic for reducing the morbidity of anxiety disorders. The associations between respiratory perturbation and REFERENCES acute anxiety are not specific to PD. In: Mills J, Mountcastle VB, Plum F, et to respiratory perturbation has also been reported in anxi- al. Baltimore: ety-disordered patients with some simple phobias, limited Williams & Wilkins, 1987:373–417. Annu Rev der, or limited-symptom anxiety attacks and in nonpsychi- Psychol 1995;46:209–235. Four systems for emotion activation: cognitive and noncognitive processes.
Induction of neurite trophic factors and their clinical implications quality careprost 3ml 7 medications that cause incontinence. J Mol Med 1997; outgrowth by MAP kinase in PC12 cells. Signal transduction by the receptor J Biol Chem 1997;272:19103–19106. The tripartite CNTF receptor com- of phospholipase C-gamma 1 activity: comparative properties plex: activation and signaling involves shared with other cyto- of control and activated enzymes. Phospholipase C-gamma as a signal-trans- STAT pathway in the developing brain. Insulin and insulin-like of the catalytic activity of phospholipase C-gamma 1 by tyrosine growth factor receptors in the nervous system. Insulin-like growth factor-I is a differen- Annu Rev Biochem 1998;67:481–507. Structure and function of phosphoinosi- precursors: distinct actions from those of brain-derived neuro- tide 3-kinases. The neurotrophic action dylinositol phosphate kinases, a multifaceted family of signaling and signalling of epidermal growth factor. Stress, glucocorticoids, and damage to the nervous inositol-3-OH kinase as a direct target of Ras. Nature 1994;370: system: the current state of confusion. Neural plasticity to stress and spinal motor neurons through activation of the phosphatidylino- antidepressant treatment. Insulin signal transduction and the expression of brain-derived neurotrophic factor and neurotro- IRS proteins. Chronic antidepressant ad- Shc have distinct but overlapping binding specificities. J Biol ministration increases the expression of cAMP response element Chem 1995;270:27407–27410. Antidepressant-like effects of ERK2 and inhibition of adenylyl cyclase in transfected CHO of BDNF and NT-3 in behavioral models of depression. Molecular mechanisms of opiate and cocaine addic- protein kinase by protein kinase C. Protein kinase C activates chiatry Clin Neurosci 1997;9:482–497. Inhibition of the EGF-activated rotrophic factors on morphine- and cocaine-induced biochemical MAP kinase signaling pathway by adenosine 3′,5′-monophos- changes in the mesolimbic dopamine system. Science 1993;262:1069–1072 biochemical and behavioral adaptations to drugs of abuse. Chapter 16: Neurotrophic Factors and Intracellular Signal Transduction Pathways 215 73. Regulation of ERK (extracellu- tributes to the initiation of behavioral sensitization to cocaine by lar signal regulated kinase), part of the neurotrophin signal trans- activating the ras/mitogen-activated protein kinase signal trans- duction cascade, in the rat mesolimbic dopamine system by duction cascade. Regulation of phospholi- regional distribution and regulation by chronic morphine. J Neu- pase C-gamma in the mesolimbic dopamine system by chronic rosci 1995;15:1285–1297. HYMAN For all living cells, regulation of gene expression by extracel- OVERVIEW OF TRANSCRIPTIONAL lular signals is a fundamental mechanism of development, CONTROL MECHANISMS homeostasis, and adaptation to the environment. Indeed, Regulation of Gene Expression by the the ultimate step in many signal transduction pathways is Structure of Chromatin the modification of transcription factors that can alter the expression of specific genes. Thus, neurotransmitters, In eukaryotic cells, DNA is contained within a discrete or- growth factors, and drugs are all capable of altering the ganelle called the nucleus, which is the site of DNA replica- patterns of gene expression in a cell. Within the nucleus, chromo- regulation plays many important roles in nervous system somes—which are extremely long molecules of DNA—are functioning, including the formation of long-term memo- wrapped around histone proteins to form nucleosomes, the ries.
In one pattern of m etabolic aci- Hyperkalemic distal tubular acidosis Alcoholism dosis buy discount careprost 3 ml online in treatment 2, the decrease in bicarbonate concentration is offset by an Early renal failure Starvation increase in the concentration of chloride, with the plasm a anion Gastrointestinal loss of bicarbonate Uremia gap rem aining norm al. In the other pattern, the decrease in bicar- Diarrhea Lactic acidosis Small bowel losses Exogenous toxins bonate is balanced by an increase in the concentration of unm ea- Ureteral diversions Osmolar gap present sured anions (ie, anions not m easured routinely), with the plasm a Anion exchange resins Methanol chloride concentration rem aining norm al. Ingestion of CaCl2 Ethylene glycol Acid infusion Osmolar gap absent HCl Salicylates Arginine HCl Paraldehyde Lysine HCl Lactic acidosis duce lactate during the course of glycolysis, those listed contribute Glucose substantial quantities of lactate to the extracellular fluid under nor- mal aerobic conditions. In turn, lactate is extracted by the liver and Gluconeogenesis to a lesser degree by the renal cortex and primarily is reconverted to glucose by way of gluconeogenesis (a smaller portion of lactate is oxidized to carbon dioxide and water). This cyclical relationship Cori between glucose and lactate is known as the Cori cycle. The basal cycle turnover rate of lactate in humans is enormous, on the order of 15 to 25 mEq/kg/d. Precise equivalence between lactate production and its use ensures the stability of plasma lactate concentration, normally M uscle Brain Skin RBC Liver Kidney cortex ranging from 1 to 2 mEq/L. Hydrogen ions (H+) released during lac- tate generation are quantitatively consumed during the use of lactate Anaerobic glycolysis H++ Lactate such that acid-base balance remains undisturbed. Accumulation of lactate in the circulation, and consequent lactic acidosis, is generated Overproduction Lactic acidosis Underutilization whenever the rate of production of lactate is higher than the rate of utilization. The pathogenesis of this imbalance reflects overproduc- tion of lactate, underutilization, or both. M ost cases of persistent lac- tic acidosis actually involve both overproduction and underutiliza- FIGURE 6-18 tion of lactate. During hypoxia, almost all tissues can release lactate Lactate-producing and lactate-consuming tissues under basal condi- into the circulation; indeed, even the liver can be converted from the tions and pathogenesis of lactic acidosis. Although all tissues pro- premier consumer of lactate to a net producer [1,14]. In PFK turn, these changes cause cytosolic accum ulation of pyruvate as a + low ATP ADP consequence of both increased production and decreased utiliza- + tion. Increased production of pyruvate occurs because the reduced NAD cytosolic supply of ATP stim ulates the activity of 6-phosphofruc- tokinase (PFK), thereby accelerating glycolysis. Decreased utiliza- tion of pyruvate reflects the fact that both pathways of its con- NADH sum ption depend on m itochondrial oxidative reactions: oxidative Pyruvate LDH Lactate decarboxylation to acetyl coenzym e A (acetyl-CoA), a reaction cat- Gluconeogenesis + alyzed by pyruvate dehydrogenase (PDH ), requires a continuous high NADH + NAD+ Cytosol supply of N AD ; and carboxylation of pyruvate to oxaloacetate, a Mitochondrial membrane reaction catalyzed by pyruvate carboxylase (PC), requires ATP. The increased [N ADH ]/[N AD+] ratio (N ADH refers to the reduced Mitochondria form of the dinucleotide) shifts the equilibrium of the lactate dehy- ATP – high NADH drogenase (LDH ) reaction (that catalyzes the interconversion of low – NAD+ ADP NAD+ pyruvate and lactate) to the right. In turn, this change coupled with Acetyl-CoA NADH the accum ulation of pyruvate in the cytosol results in increased Oxaloacetate TCA accum ulation of lactate. Despite the prevailing m itochondrial dys- – cycle function, continuation of glycolysis is assured by the cytosolic regeneration of N AD+ during the conversion of pyruvate to lactate. Provision of N AD+ is required for the oxidation of glyceraldehyde FIGURE 6-19 3-phosphate, a key step in glycolysis. Thus, lactate accum ulation H ypoxia-induced lactic acidosis. Accum ulation of lactate during can be viewed as the toll paid by the organism to m aintain energy hypoxia, by far the m ost com m on clinical setting of the disorder, production during anaerobiosis (hypoxia). ADP— adenosine originates from im paired m itochondrial oxidative function that diphosphate; TCA cycle— tricarboxylic acid cycle. FIGURE 6-20 CAUSES OF LACTIC ACIDOSIS Conventionally, two broad types of lactic acidosis are recognized. In type A, clinical evidence exists of impaired tissue oxygena- Type A: tion. Impaired Tissue Oxygenation Type B: Preserved Tissue Oxygenation Occasionally, the distinction between the two types may be less than obvious. Thus, Shock Diseases and conditions Drugs and toxins inadequate tissue oxygenation can at times Severe hypoxemia Diabetes mellitus Epinephrine, defy clinical detection, and tissue hypoxia Generalized convulsions Hypoglycemia norepinephrine, can be a part of the pathogenesis of certain Vigorous exercise Renal failure vasoconstrictor agents causes of type B lactic acidosis. M ost cases Exertional heat stroke Hepatic failure Salicylates of lactic acidosis are caused by tissue hypox- Hypothermic shivering Severe infections Ethanol ia arising from circulatory failure [14,15]. Massive pulmonary emboli Alkaloses Methanol Severe heart failure Malignancies (lymphoma, Ethylene glycol Profound anemia leukemia, sarcoma) Biguanides Mesenteric ischemia Thiamine deficiency Acetaminophen Carbon monoxide poisoning Acquired Zidovudine Cyanide poisoning immunodeficiency syndrome Fructose, sorbitol, Pheochromocytoma and xylitol Iron deficiency Streptozotocin D-Lactic acidosis Isoniazid Nitroprusside Congenital enzymatic defects Papaverine Nalidixic acid 6. M anagem ent • Dialysis (toxins) of lactic acidosis should focus prim arily on • Discontinuation of incriminated securing adequate tissue oxygenation and on drugs No • Insulin (diabetes) aggressively identifying and treating the Inadequate tissue Cause-specific measures underlying cause or predisposing condition. In the presence of • Low carbohydrate diet and Oxygen-rich mixture antibiotics (D-lactic acidosis) severe or worsening m etabolic acidem ia, and ventilator support, Circulatory failure?